Cancer Genetics Program - Project Summary/Abstract Cancer is, at its most fundamental level, a disease of the genome. The central goal of the Cold Spring Harbor Laboratory (CSHL) Cancer Genetics Program (CG) is to use information contained within the cancer genome to improve our understanding and treatment of the disease. Our multifaceted approach includes mapping the specific pathways involved in different forms of cancer, developing new diagnostic markers and therapeutic strategies for cancer cells, and technology development for monitoring the progression of the disease. Many members maintain strong research programs in the discovery of cancer-specific variations, ranging from single nucleotide and small indel polymorphisms to copy number changes to modification of the epigenome. A particular strength of the CG Program is in the analysis of the heterogeneity of tumors revealed through single cell analysis. This heterogeneity is proving to be especially important in the clinical setting as it often contributes to disease progression and therapy resistance. Complementary to the experimental strengths of the Program, the Program is also expert at developing computational approaches to identify and model the most important alterations. Drivers of tumor development are functionally validated, most often in the mouse, using strategies, many developed within the CG Program, which encompass chromosome engineering (e.g., for copy number or structural variations), mosaic mouse models with expressed oncogenes and tumor suppressors regulated in vivo with shRNAs. Completely unbiased functional approaches are also taken by several groups to discover novel therapeutic targets using well characterized cultured cell lines, mosaic animal models, and primary patient tumor grafts. Finally, several CG Program investigators approach the problem of cancer prevention by looking at genetic and behavioral modifiers of risk. The premier position of CG Program investigators in employing many of these strategies is recognized by their lead involvement in national projects including the Mouse Models of Human Cancer Consortium (MMHCC), the cancer genome atlas (TCGA), Stand Up to Cancer, the Leukemia and Lymphoma Society program projects, the STARR consortium, as well as many similar awards from the NCI, the NIH, the DOD, and the NSF. The CG Program has sixteen members. As of 8/1/15, CG members received $2.3M in direct support from NCI and other peer-reviewed sources, and $0.8M in additional cancer-related support. Since 9/1/10, the CG Program published 148 cancer-related articles, 49 (33%) involved multiple CCSG members; 29 (20%) intra- programmatic, and 25 (17%) inter-programmatic. Forty CG publications appeared in the highest profile journals (Science, Cell and Nature families). During the next five years, the CG Program will continue its tradition of innovation and impact, but in a manner that will require continued support of the CSHL Cancer Center.